Results from the World Health Organization MONICA Project confirm that coronary artery disease resulting from atherosclerosis is the major determinant of mortality in the Western population. Vascular injury leading to the production of cell activating factors such as thrombin and the ensuing robust vasculoproliferative response is a major contributory mechanism in the production of occlusive coronary lesions. Though many pathways lead to atherogenesis, oxidative stress and oxidative signaling have been demonstrated to provide a common link. In the previous grant period, we focused on the mechanisms by which ROS are produced in the vessel wall, studying the molecular events that occur following interaction of thrombin with its receptors on vascular cells. The goal of this proposal is to examine the relationship between ROS and atherogenesis, with the overall goal of defining the mechanisms by which vascular cells generate ROS and ROS-mediated molecular events that contribute to normal and pathologic vascular formation. Our specific aims to: 1) determine the thrombin-mediated molecular events that result in NADPH oxidase activation in VSMC, and whether other mediators (such as Angiotensin II and TNF-alpha) utilize common signaling mechanisms; 2) determine the balance between oxidative stress and protective responses in VSMC and their relative roles in atherosclerosis; and 3) identify genetic factors that influence susceptibility to oxidative stress and atherosclerosis. These studies will elucidate common mechanisms in atherosclerosis that regulate intracellular ROS production and vascular cell growth, hopefully leading to the identification of new, highly specific targets for therapeutic intervention.